FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells.
Fas-associated death domain protein (FADD) and caspase-8 (casp8) are vital intermediaries in apoptotic signaling induced by tumor necrosis factor family ligands. Paradoxically, lymphocytes lacking FADD or casp8 fail to undergo normal clonal expansion following antigen receptor cross-linking and succumb to caspase-independent cell death upon activation. Here we show that T cells lacking FADD or casp8 activity are subject to hyperactive autophagic signaling and subvert a cellular survival mechanism into a potent death process. T cell autophagy, enhanced by mitogenic signaling, recruits casp8 through interaction with FADD:Atg5-Atg12 complexes. Inhibition of autophagic signaling with 3-methyladenine, dominant-negative Vps34, or Atg7 shRNA rescued T cells expressing a dominant-negative FADD protein. The necroptosis inhibitor Nec-1, which blocks receptor interacting protein kinase 1 (RIP kinase 1), also completely rescued T cells lacking FADD or casp8 activity. Thus, while autophagy is necessary for rapid T cell proliferation, our findings suggest that FADD and casp8 form a feedback loop to limit autophagy and prevent this salvage pathway from inducing RIPK1-dependent necroptotic cell death. Thus, linkage of FADD and casp8 to autophagic signaling intermediates is essential for rapid T cell clonal expansion and may normally serve to promote caspase-dependent apoptosis under hyperautophagic conditions, thereby averting necrosis and inflammation in vivo.
Bell
Bryan D
BD
Department of Molecular Biology and Biochemistry and Center for Immunology, University of California, Irvine, Irvine, CA 92697-3900, USA.
Leverrier
Sabrina
S
Weist
Brian M
BM
Newton
Ryan H
RH
Arechiga
Adrian F
AF
Luhrs
Keith A
KA
Morrissette
Naomi S
NS
Walsh
Craig M
CM
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D053181:Caspase 8 / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000502:physiology*; D025461:Feedback, Physiological; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology*
D053200:Fas-Associated Death Domain Protein; D053181:Caspase 8